ABSTRACT This proposal focuses on developing amodiaquine (AQ), a FDA approved antimalarial medication, as a multi-target therapy for pulmonary arterial hypertension (PAH). PAH-associated severe increase in pulmonary blood pressure is caused by obstruction in blood flow via pulmonary vasculature primarily by uncontrolled growth and proliferation in cellular layers of vessel walls and accumulation of inflammatory markers resulting in development of thrombus and plexiform lesions. Despite significant advances in PH drug discovery, a submissive improvement has been seen in therapeutic outcomes and overall patient survival. Poor survival benefits in PAH patients can be attributed to lack of therapies targeting multiple overlapping pathological pathways to subside disease progression. Two phenomena responsible for regulating cellular death and proliferation, Apoptosis (programmed cell death) and Autophagy (self- digestion), have been found to be vastly dysregulated in PAH. Disease progression is shown to be associated with lack of apoptosis and hyperactive autophagy in pulmonary vasculature, thus resulting in uncontrolled hyper-proliferation of vascular smooth muscle and endothelial cells. Amodiaquine (AQ), A previously FDA approved antimalarial, is a known autophagy inhibitor, with some studies outlining its efficacy in jumpstarting apoptotic mechanisms in-vitro. Preliminary data indicated AQ's efficacy in controlling cellular proliferation and treating PAH symptoms in monocrotaline rat model. In this proposal, we hypothesize that amodiaquine exhibits its anti-PAH effects by targeting autophagy flux and apoptotic induction simultaneously so as to provide therapeutic benefits in PAH progression. To test this hypothesis, we will determine its efficacy and mechanism of action of AQ in relevant in-vitro and in-vivo models. In-vitro efficacy and mechanistic studies will be performed in primary human pulmonary artery smooth muscle and endothelial cells. Findings from in-vitro studies will be confirmed in- vivo in SU5416/hypoxia induced rat model of pulmonary hypertension which mimics pathophysiological features of the human disease. Pharmacokinetic profiling of AQ will be performed in both healthy and diseased Sprague-Dawley rats to determine the dosing for efficacy studies. Further studies will be performed SU5416/hypoxia induced rats to confirm (i) preventative, (ii) therapeutic, and (iii) disease reversal properties of amodiaquine. Hemodynamic and molecular mechanistic data obtained from small animal studies will be pivotal in providing insights about amodiaquine's efficacy and mechanism of action. Long-term impacts of this project's success will be immense. Success of these studies will ascertain availability of an affordable PAH therapy, capable of not only reducing the symptoms but also restraining disease progression for improved patient survival, quality of life, and therapeutic outcomes. A shorter development cycle will qualify AQ to be available at affordable costs while affirming its wide-spread reach.